One way of examining the function and performance of a patient's heart is by determining the cardiac output, i.e. the amount of blood pumped by the left ventricle per unit time. A well-established method to measure the cardiac output is by inert gas rebreathing, which is a non-invasive measurement method to determine pulmonary blood flow. The pulmonary blood flow is equal to the cardiac output in the absence of a significant intrapulmonary shunt.
The method uses a mixture containing two inert gases, a blood soluble and a blood insoluble compound. The blood soluble gas and preferably also the insoluble gas are not present in ambient or normal expired air. Blood soluble gases that can be used in inert gas rebreathing tests are e.g. nitrous oxide, acetylene and chlorodifluoromethane (Freon 22). The principle of the method is to have the patient inhale the gas mixture from a rebreathing bag and breathe the gas mixture in a closed rebreathing assembly for a short period of time (e.g. 10-15 seconds) (here and in the following called a rebreathing test or rebreathing period). When the blood soluble compound comes in contact with the blood perfusing the lungs it is absorbed and therefore gradually disappears from the rebreathing assembly. The faster the blood flows, the quicker the blood soluble gas disappears.
The blood insoluble compound is used to determine the lung volume, which is an important variable in the relationship between the disappearance rate of the blood soluble gas and pulmonary blood flow. It is also used as a tracer substance to account for various basic assumptions of the underlying lung model. Thus, the measurement of cardiac output or pulmonary blood flow is a matter of measuring the rate of disappearance of blood soluble gas from the rebreathing system and the dilution of insoluble gas.
Non-invasive measurement of cardiac output or pulmonary blood flow by inert gas rebreathing is important in a variety of clinical settings where invasive methods should be avoided or where other non-invasive methods are e.g. either unreliable or impractical.
One of the main assumptions of the inert gas rebreathing method to measure pulmonary blood flow is that the partial pressure of the inert blood soluble compound in the mixed venous blood is zero during the test.
This assumption is correct when a patient is doing the first test in a series of tests. However, if subsequent tests are done with only a short time period between tests the assumption becomes invalid. This is because a small amount of the blood soluble gas is absorbed by the blood perfusing the lungs during a test and subsequently deposited in various tissues in the body. Between the tests (called a washout period) the deposited gas however diffuses back into the blood and is carried to the lungs in the mixed venous blood. Thus the partial pressure of the soluble gas in the mixed venous blood is no longer zero as assumed in the model. This situation is referred to as recirculation.
In order to avoid this problem the patient must be allowed enough time between two tests for the blood soluble gas to be washed out. This can be obtained with a break of around 5-10 minutes if the patient is relaxing or approximately 2-5 minutes during exercise. This obviously results in dramatically prolonged duration of the testing time needed for each patient and also adds considerably to the overall cost of performing the test. Furthermore, simply prolonging the tests in order to ensure that all the blood soluble gas is washed out is also not optimal in the case of the tests being performed while the patient is exercising. Here, a significant prolongation of the test would eventually lead to the patient getting exhausted too early which is undesirable. Also, in several clinical applications it is essential to do frequent measurements of the pulmonary blood flow in order to see and measure the immediate effect of different interventions such as adjustments of a biventricular pacemaker etc. In these cases the measured pulmonary blood flow hence becomes inaccurate as the aforementioned assumption of zero partial pressure of the blood soluble compound in mixed venous blood may no longer be valid.
Whether the mixed venous partial pressure of the blood soluble gas is non-zero can be seen in the expired air (end-tidal partial pressure of the gas) prior to the start of the rebreathing test provided that the gas analyzer is sufficiently sensitive to detect the trace amount of the blood soluble gas. However, the size of the mixed venous partial pressure of the blood soluble gas can not be measured directly by noninvasive means and even if it could the parameter is not used in the methods to determine the pulmonary blood flow as of the state of art.
Simulations have shown that the error on the measured blood flow can be quite significant if the mixed venous blood content is non-zero. The error is almost proportional to the ratio between the steady-state end-tidal level of blood soluble gas prior to rebreathing and the initial content in the rebreathing bag so that for each percent of this ratio the error (underestimation) is approximately 10% (simulation done with a resting blood flow of 5 l/min, a lung volume equal to the bag volume of 2 l, and an alveolar ventilation of 7 l/min). If a test is repeated after e.g. 30 seconds the error can easily be in the order of 30%. This again leads to an unacceptable uncertainty in the diagnosis or treatment of the patient.
The problem of recirculation is seldom considered in the known art. In U.S. Pat. No. 4,363,327 the pulmonary blood flow is determined based on a number of repeated washin and washout periods. According to the document a cyclical injection of the blood soluble and insoluble inert gases is causing a cyclic steady-state whereby the changes in the venous concentrations of the soluble gas over a cycle period become small. The method is indifferent to unknown but slowly varying concentrations of soluble gases in the venous system, and the pulmonary blood flow is determined based on this observation. However, in order to realize this steady-state the method necessitates a rather large number of near-identical cycles (up to 30) to be performed before giving reliable results and further does not deal with how to compensate for incomplete washout of blood soluble gas in between measurements but rather describes a method which produces a significant venous return of the soluble gas.
In the paper by Balouch et al. (“The effect of incomplete acetylene washout on cardiac output measurement using open circuit acetylene uptake”, Respir. Physiol. Neurobiol., 2006 May 19) the effect of incomplete acetylene washout on cardiac output measurement is considered during open circuit acetylene uptake. The calculation of the cardiac output is here determined by applying a correction factor estimating the mixed venous acetylene concentration from end-tidal values. As such the paper deals with the same basic problem of incomplete washout of blood soluble gas in between measurements of cardiac output. However, the method is applicable to open circuit acetylene uptake and can not readily be applied to the inert gas rebreathing method from which it differs in several ways. First, the open circuit method uses washin of a gas mixture through a one-way valve whereas the rebreathing method uses a closed system. Second, the method is more sensitive to inhomogeneities in the lungs because rebreathing is a more effective maneuver to obtain good mixing of the gases. Third, the washin period of the blood soluble gas is much longer than the rebreathing period and furthermore, the washin requires much more inert gas than rebreathing which makes the equipment more bulky and the procedure more expensive.